Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism.

Autor: Kotan LD; Division of Pediatric Endocrinology, Cukurova University, Faculty of Medicine, Adana, Turkey., Ternier G; Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, Lille, France., Cakir AD; Division of Pediatric Endocrinology, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey., Emeksiz HC; Division of Pediatric Endocrinology, Istanbul Medeniyet University, Faculty of Medicine, Istanbul, Turkey., Turan I; Division of Pediatric Endocrinology, Cukurova University, Faculty of Medicine, Adana, Turkey., Delpouve G; Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, Lille, France., Kardelen AD; Division of Pediatric Endocrinology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey., Ozcabi B; Division of Pediatric Endocrinology, Health Sciences University, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey., Isik E; Clinic of Pediatric Endocrinology, Afyonkarahisar State Hospital, Afyonkarahisar, Turkey., Mengen E; Clinic of Pediatric Endocrinology, Ankara City Hospital, Children's Hospital, Ankara, Turkey., Cakir EDP; Division of Pediatric Endocrinology, Health Sciences University, Istanbul Bakırkoy Dr. Sadi Konuk Research and Training Hospital, Istanbul, Turkey., Yuksel A; Clinic of Pediatric Endocrinology, Health Sciences University, Derince Training and Research Hospital, Kocaeli, Turkey., Agladioglu SY; Clinic of Pediatric Endocrinology, Memorial Hospital, Istanbul, Turkey., Dilek SO; Division of Pediatric Endocrinology, Cukurova University, Faculty of Medicine, Adana, Turkey., Evliyaoglu O; Division of Pediatric Endocrinology, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey., Darendeliler F; Division of Pediatric Endocrinology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey., Gurbuz F; Division of Pediatric Endocrinology, Cukurova University, Faculty of Medicine, Adana, Turkey., Akkus G; Division of Endocrinology and Metabolism, Cukurova University, Faculty of Medicine, Adana, Turkey., Yuksel B; Division of Pediatric Endocrinology, Cukurova University, Faculty of Medicine, Adana, Turkey., Giacobini P; Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, Lille, France. paolo.giacobini@inserm.fr., Topaloglu AK; Department of Pediatrics, Division of Pediatric Endocrinology, University of Mississippi Medical Center, Jackson, MS, USA. ktopaloglu@umc.edu.; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA. ktopaloglu@umc.edu.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Jun; Vol. 23 (6), pp. 1008-1016. Date of Electronic Publication: 2021 Jan 25.
DOI: 10.1038/s41436-020-01087-5
Abstrakt: Purpose: Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH.
Methods: We screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development.
Results: We identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons.
Conclusion: SEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.
Databáze: MEDLINE
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